Intestinal parasites infect more than 1 billion people worldwide and are especially common in developing countries where total food consumption is often limited. Chronic calorie restriction (CR) is prolonged low calorie intake without malnutrition. CR has many physiological benefits, including enhanced immune function as tested with antigens and mitogens. It is expected that chronic CR also increases resistance to intact pathogen infection. Surprisingly, recent research shows that chronic CR increases susceptibility to infection despite adequate immune responses. The long-term research goal of this project is to determine if the increased susceptibility to intestinal parasite infection that occurs during chronic CR is related to changes in the host-parasite reactive oxygen species (ROS)/antioxidant pathway. The overall hypothesis is that CR increases susceptibility to intestinal parasite infection because CR alters the balance between ROS and antioxidants that are necessary for host defense against an intact pathogen. This hypothesis is based on the observations that (1) caloric restricted mice harbor more worms than fully fed mice despite adequate immune response of cytokines and immunoglobins, (2) host defense against nematode worms includes the use of ROS, and (3) caloric restriction typically decreases production of ROS and alters production of associated antioxidants. The three specific aims of this project are: Specific Aim 1: To measure immune response after long- term calorie restriction for mouse strains that are either susceptible or resistant to chronic Heligmosomoides bakeri infection; Specific Aim 2: To measure production of ROS and antioxidants in worms and mice; and Specific Aim 3: To measure in vitro susceptibility of helminth worms to ROS and lipid peroxidation of worms in vitro and in vivo. Experiments will be accomplished by infecting two inbred mouse strains (C57BL/6 and SJL) with the intestinal nematode Heligmosomoides bakeri. Eight measures of immune function will be measured with ELISA, eosinophil counts, and CD4+ T cell isolation by positive selection. ROS, antioxidants, and lipid peroxidation will be measured using ELISA and mature worms will be removed from mice, measured and then placed in culture media to determine worm survival and egg output. This research will have important implications for human health because (1) millions of people live with adequate nutrition but with low food availability and high parasite prevalence, (2) pharmaceutical mimics of caloric restriction are being researched and developed to slow aging but caution may be needed before dissemination to the public if their use might increase pathogen susceptibility, and (3) if calorie intake of a host can affect parasite survival and reproduction this will alter host-pathogen transmission dynamics that contribute to the world wide infection of people by intestinal parasites. Public Health Relevance: This research will have important implications for human health because (1) millions of people live with adequate nutrition but with low food availability and high parasite prevalence, (2) pharmaceutical mimics of caloric restriction are being researched and developed to slow aging but caution may be needed before dissemination to the public if their use might increase pathogen susceptibility, and (3) if calorie intake of a host can affect parasite survival and reproduction this will alter host-pathogen transmission dynamics that contribute to the world wide infection of people by intestinal parasites.